Pharmaceutical compositions containing quaternary ammonium compounds

ABSTRACT

Quaternary ammonium carbamate, thiocarbamate, dithiocarbamate and carbamide compounds. Typical examples are 
     [C 4  H 9  NHCOO(CH 2 ) 2  N + (CH 3 ) 2  C 12  H 25  ]Br -   
     [C 4  H 9  NHOSO(CH 2) 2  N + (CH 3 ) 2  C 12  H 25  ]Br -   
     [CH 3  NHCSS(CH 2 ) 2  N + (CH 3 ) 2  C 12  H 25  ]Br -   
     [C 2  H 5  NHCONH(CH 2 ) 2  N + (CH 3 ) 2  C 12  H 25  ]Br - .

This is a divisional of application Ser. No. 134,827 filed Apr. 16,1971, which is a divisional of Ser. No. 712,968 filed Mar. 14, 1968 nowU.S. Pat. No. 3,621,048 granted Nov. 16, 1971 which is a CIP of Ser. No.578,981 filed Sept. 13, 1966, now abandoned.

The present invention relates to novel quaternary ammonium compoundsand, more particularly, to quaternary ammonium compounds containing acarbamate, or a thiocarbamate, or a dithiocarbamate, or a carbamidegroup. The novel quaternary ammonium compounds of the present inventionare useful in reducing caries, inhibiting acid formation in the oralcavity, in inhibiting formation of oral calculus, and/or as effectivefungicides.

Novel compounds of the invention are superior to quaternary ammoniumcompounds, to carbamates and to thiocarbamates previously known to havesome efficacy in in vitro anti-caries tests. They also reduce caries andinhibit formation in vivo in mammals.

It has been discovered that quaternary ammonium compounds having acarbamate, or a thiocarbamate, or a dithiocarbamate, or a carbamidegroup have greatest usefulness as bactericides against gram-positiveorganisms and as fungicides and as effective anti-caries and calculusinhibiting agents. The compounds of the present invention can berepresented by the following formula: ##STR1## wherein R' is selectedfrom the group consisting of an alkyl group containing 1 to 22 carbonatoms, an aryl group, an aryl group substituted by halogen, i.e., Cl,Br, F, I, an aryl group substituted by alkyl containing 1 to 5 carbonatoms, and an aryl group substituted by alkoxy containing 1 to 5 carbonatoms;

R" and R'" are each selected from the group consisting of acyclicaliphatic hydrocarbon radicals having 1 to 2 carbon atoms andhydrocarbon radicals that form a ring system including the (CH₂)_(n) Ngroup and R" and R'";

R"" is an alkyl group containing 1 to 22 carbon atoms, an aryl groupsubstituted by halogen, i.e., Cl, Br, F, I; an aryl group substituted byalkyl containing 1 to 5 carbon atoms; an aryl group substituted byalkoxy group containing 1 to 5 carbon atoms, divalent aliphatic groupshaving up to 10 carbon atoms, divalent aryl groups, monovalent arylgroup;

Y is selected from the group consisting of oxygen and sulfur;

Z is selected from the group consisting of oxygen, NH and sulfur;

X is a compatible anion such as Cl⁻, Br⁻, I⁻, SO₄ Me^(-;) and n is aninteger 2 to 6.

When the --(CH₂)_(n) NR"R'"-- groups form a ring system, typically thering system is quinuclidine ##STR2## or piperidine, ##STR3##

When the --(CH₂)_(n) NR"R'"-- groups do not form a ring system, R" andR'" may be the same or different; that is, both may be CH₃, or both maybe C₂ H₅ or one may be CH₃ and the other C₂ H₅.

It is to be observed that the compounds generally described by theforegoing formula are effective against gram positive organisms such asStaph. aureus, Str. mitis S-3, Bacillus subtilis, Corynebacterium acnes,and against fungi, such as Candida albicans and Trichophytonmentagrophytes. Of the compounds represented by the general formulagiven hereinbefore, those compounds in which either R' or R"" is a longchain alkyl group (10-16 carbon atoms) and the other of R' and R"" is ashort chain alkyl (1 to 4 carbon atoms) or aryl, or aralkyl groupcontaining 1 to 5 carbon atoms in the alkyl moiety are particularlyeffective against gram-positive organisms. Of the compounds representedby the general formula provided hereinbefore, the compounds particularlyeffective against fungi are those in which R' is an aromatic group andparticularly an aryl group or an aryl group substituted by halogen, andR"" is a long chain alkyl group (10 to 18 carbon atoms).

The compounds of the invention which are most effective in reducingcaries and inhibiting formation of oral calculus are those in which R""is a long alkyl chain having 10 to 16 carbon atoms. The compounds of thegeneral formula given herein which are most effective in in vitroanti-caries are those in which one of R' or R"" is a long alkyl chain of10 to 14 carbon atoms and the other of R' or R"" is an aryl group or ahalogen-substituted aryl group or short alkyl chain of 1 to 4 carbonatoms and n is in the range of 2 to 6.

The thiocarbamate compounds can be prepared by converting the aminoalcohol to the sodium salt thereof with metallic sodium in any suitablemanner. An isothiocyanate is reacted with the aforesaid sodium salt. Thereaction product is isolated in any suitable manner and quaternized withan alkylhalide or aralkyl halide.

The carbamate compounds can be prepared by reacting an isocyanate withthe aminoalcohol, followed by quaternization with an alkyl or aralkylhalide.

The dithiocarbamate compounds can be prepared by reacting anisothiocyanate with the sodium salt of the aminoalkanethiol followed byquaternization with an alkyl or aralkyl halide.

The carbamide compounds can be prepared by reacting an isocyanate withthe alkanediamine followed by quaternization with an alkyl or aralkylhalide.

The following examples illustrate the manner in which compounds of theinvention are prepared.

EXAMPLE 1

2-hydroxyethyl dimethyldodecylammonium bromide, N-butylthiocarbamate isprepared in the following manner: Sodium (0.095 gr. atom) was powderedunder 100 milliliters of xylene. 2-dimethylaminoethanol (0.095 mole) wasadded during 10 minutes and the mixture stirred until the sodiumdissolved. Normal butyl isothiocyanate (0.10 mole) was added at roomtemperature (about 75° F.). After standing at ambient temperature (about75° F.) for about 80 minutes the reaction mixture was poured into about500 milliliters of water and the resultant slurry neutralized with 16milliliters of concentrated hydrochloric acid. After removing thexylene, the aqueous layer was washed with diethyl ether and then madebasic with sodium hydroxide. The oil is extracted with ether andrecovered by evaporation or distillation of the ether. The residue,i.e., the product, O-(2-dimethylaminoethyl) N-butylthiocarbamate has aneutral equivalent of 205 (theory 204.3). A portion of the amine soobtained (0.01 mol) was mixed with 0.01 mol of 1-bromododecane and keptat ambient (room temperature -75° F.) for 2 weeks. The resultantcrystalline mass was triturated with diethyl ether leaving 4.1 grams ofproduct which was recrystallized from 30 milliliters of ethyl acetate,i.e., about seven times as much ethyl acetate as product by weight. Therecovered crystals weighed 3.6 grams and had a melting point of 91° to93° C.

    ______________________________________                                        Analysis for C.sub.21 H.sub.45 Br N.sub.2 OS                                  Calculated                 Found                                              ______________________________________                                        55.61%       Carbon        55.07%                                             10.00%       Hydrogen      10.01%                                              6.18%       Nitrogen       6.04%                                             ______________________________________                                    

The infrared and nuclear magnetic resonance spectra agree with thefollowing structural formula: ##STR4##

The thiocarbamate compounds for which structural formulas are given inthe table below have been similarly prepared. All aromatic substitutionis para. Thus, ##STR5## (compound 23 in the table below) is preparedusing ethyl isothiocyanate in place of normal butyl isothiocyanate.

EXAMPLE 2

2-hydroxyethyldimethyldodecylammonium bromide, N-butylcarbamate isprepared in the following manner: A solution of 58 g. (0.65 mole)2-dimethylaminoethanol in 150 ml. ether was treated over a period of 1.5hours with 70 g. (0.71 mole) n-butyl isocyanate. After stirring anothertwo hours the reaction mixture was stripped of ether and distilled invacuum. The product, 2-dimethylaminoethyl N-butylcarbamate was collectedat 106°/1.2 Torr. For quaternization 75 g. (0.40 mole) of the aboveprepared amine was combined with 105 g (0.42 mole) 1-bromododecane andallowed to stand stoppered for nine days. At this time the reactionmixture was a stiff gel with some crystalline portions. By solution inethyl acetate (900 ml.) and chilling, 160 g. of product was obtained incrystalline form. After two more recrystallizations from ethyl acetate,the material melted at 64° C. to liquid crystals and to a liquid at 115°C.

Analysis for C₂₁ H₁₅ BrN₂ O₂

    ______________________________________                                        Analysis for C.sub.21 H.sub.15 BrN.sub.2 O.sub.2                              Calculated                 Found                                              ______________________________________                                        57.65        Carbon        57.87                                              10.37        Hydrogen      10.82                                              ______________________________________                                    

The infrared and nuclear magnetic resonance spectra agree with thefollowing structural formula: ##STR6##

The carbamate compounds for which structural formulas are given in thetable below have been similarly prepared. All aromatic substitution ispara.

EXAMPLE 3

2-(Methyldithiocarbamyl) ethyldimethyldodecylammonium bromide wasprepared as follows: A solution of 15.0 g. (0.105 mole) of2-dimethylaminoethanethiol hydrochloride in 15 ml. of water wasneutralized with 210 ml. of 1N sodium hydroxide solution and thentreated immediately with 8.1 g. (0.11 mole) of methyl isothiocyanatedissolved in a few ml. of methanol. Following 30 minutes of stirring atroom temperature, the reaction mixture was treated with 105 ml. of 1Nhydrochloric acid. After 1 hour the precipitated solid was removed byfiltration, dried, and recrystallized from benzene-Skellysolve B. Theyield was 9.7 g. (54%), mp. 110°-112°.

A solution of 3.0 g. (0.017 mole) of the above-prepared2-dimethylaminoethyl methyldithiocarbamate and 4.2 g. (0.017 mole) of1-bromododecane in 25 ml. acetone was prepared and set aside for twoweeks. The solid mass which had formed was recrystallized from anhydrous3A alcohol, to recover 4.3 g. mp 174°-175°.

Analysis for C₁₈ H₃₉ BrN₂ S₂

    ______________________________________                                        Analysis for C.sub.18 H.sub.39 BrN.sub.2 S.sub.2                              Calculated                 Found                                              ______________________________________                                        50.56        Carbon        51.31                                               9.19        Hydrogen       9.30                                               6.55        Nitrogen       6.54                                              ______________________________________                                    

The infrared and nuclear magnetic resonance spectra agree with thefollowing structural formula: ##STR7##

EXAMPLE 4

2-(Ethylureido)ethyldimethyldodecylammonium bromide was prepared asfollows: Five grams (0.057 mole) of N,N-dimethylethylenediaminedissolved in 10 ml. of ether was treated dropwise with 4.3 g. (0.06mole) of ethyl isocyanate dissolved in 10 ml. of ether. After 15 minutesthe reaction mixture was diluted with more ether and saturated withhydrogen chloride gas. The precipitate was triturated with acetone anddried. In titrating with sodium chloride two end points were observedindicating it was the dihydrochloride of1-ethyl-3-(2-dimethylaminoethyl)urea. By neutralization with sodiumhydroxide, evaporation, extraction with ether, and evaporation 5.5 g. offree base was obtained.

1.6 g. (0.01 mole of the above prepared amine and 2.5 g. (0.01 mole)1-bromododecane were dissolved in 25 ml. acetone and allowed to standovernight. The mixture was then refluxed for 31/2 hours. Evaporation ofthe solvent left a mixture of product and starting materials which wasseparated by ether extraction, the product being insoluble. The 1.6 g.material so obtained was recrystallized from ethyl acetate, m.p.93.5°-95.3°.

Analysis for C₁₉ H₄₂ BrN₃ O

    ______________________________________                                        Analysis for C.sub.19 H.sub.42 BrN.sub.3 O                                    Calculated                 Found                                              ______________________________________                                        55.86        Carbon        55.78                                              10.37        Hydrogen      10.95                                              10.29        Nitrogen      10.20                                              ______________________________________                                    

The infrared and nuclear magnetic resonance spectra agree with thefollowing structural formula: ##STR8##

The following table lists additional compounds of the invention:

                                      Table                                       __________________________________________________________________________                                Melting Point                                     No.                                                                              Compound                 Degrees Centigrade                                __________________________________________________________________________     5 [C.sub.6 H.sub.5 NHCOO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2               CH.sub.2 C.sub.6 H.sub.4 Br] Br.sup.-                                                                  186-188                                            6 [C.sub.6 H.sub.5 NHCOO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2               C.sub.12 H.sub.25 ] Br.sup.-                                                                           144-145                                            7 [ClC.sub.6 H.sub.4 NHCOO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2             CH.sub.2 C.sub.6 H.sub.4 Cl] Cl.sup.-                                                                  207-208                                            8 [ClC.sub.6 H.sub.4 NHCOO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2             CH.sub.2 C.sub.6 H.sub.4 Br] Br.sup.-                                                                  199.5-201                                          9 [ClC.sub.6 H.sub.4 NHCOO(CH.sub.2).sub.6 N.sup.+ (CH.sub.3).sub.2             CH.sub.2 C.sub.6 H.sub.4 Br] Br.sup.-                                                                  188.5-190                                         10 [ClC.sub.6 H.sub.4 NHCOO(CH.sub.2).sub.6 N.sup.+ (CH.sub.3).sub.2             C.sub.12 H.sub.25 ] Br.sup.-                                                                           104-105.3                                         11 [ClC.sub.6 H.sub.4 NHCOO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3 ).sub.2            (CH.sub.2).sub.5 ].sub.2 Br.sub.2 .sup.-                                                               213-215                                           12 [ClC.sub.6 H.sub.4 NHCSO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2             CH.sub.2 C.sub.6 H.sub.4 Cl] Cl.sup.-                                                                  162-163                                           13 [ClC.sub.6 H.sub.4 NHCSO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2             CH.sub.2 C.sub.6 H.sub.4 Br] Br.sup.-                                                                  178.5-179.5                                       14 [ClC.sub.6 H.sub.4 NHCSO(CH.sub.2).sub.3 N.sup.+ (CH.sub.3).sub.2             CH.sub.2 C.sub.6 H.sub.4 Br] Br                                                                        152-154                                           15 [ClC.sub.6 H.sub.4 NHCSO(CH.sub.2).sub.6 N.sup.+ (CH.sub.3).sub.2             CH.sub.2 C.sub.6 H.sub.4 Br] Br.sup.-                                                                  167.5-168.5                                       16 [ClC.sub.6 H.sub.4 NHCSO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2             C.sub.12 H.sub.25 ] Br.sup.-                                                                           140.5-142.5                                       17 [ClC.sub.6 H.sub.4 NHCSO(CH.sub.2).sub.3 N.sup.+ (CH.sub.3).sub.2             C.sub.12 H.sub.25 ] Br.sup.-                                                                           150-151                                           18 [ClC.sub.6 H.sub.4 NHCSO(CH.sub.2).sub.6 N.sup.+ (CH.sub.3).sub.2             C.sub.12 H.sub.25 ]  Br.sup.-                                                                          106-108.5                                         19 [ClC.sub.6 H.sub.4 NHCSO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2             C.sub.18 H.sub.37 ] Br.sup.-                                                                           146-150                                           20 [C.sub.12 H.sub.25 NHCSO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2             CH.sub.2 C.sub.6 H.sub.4 Br] Br.sup.-                                                                  118.5-120.5                                       21 [C.sub.12 H.sub.25 NHCSO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.3]            I.sup.-                  170-172                                           22 [CH.sub.3 NHCSO(CH.sub.2).sub.2 N.sup.+ (CH.sub.3).sub.2 C.sub.12             H.sub.25 ] Br.sup.-      73.0-75.5                                         23 [C.sub.2 H.sub.5 NHCSO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2                C.sub.12 H.sub.25 ] Br.sup.-                                                                           94.5-97.0                                         24 [C.sub.4 H.sub.9 NHCSO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2                C.sub.10 H.sub.21 ] Br.sup.-                                                                           93-96                                             25 [C.sub.4 H.sub.9 NHCSO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2                C.sub.14 H.sub.29 ] Br.sup.-                                                                           94-96                                             26 [CH.sub.3 NHCSO(CH.sub.2).sub.6 N.sup.+(CH.sub.3).sub.3 ] I.sup.-                                      115.5-117                                         27 [CH.sub.3 NHCSO(CH.sub.2).sub.6 N.sup.+(CH.sub.3).sub.2 C.sub.12              H.sub.25 ] Br.sup.-      81.5- -28 [C.sub.2 H.sub.5 NHCSO(CH.sub.2).sub                                .2 N.sup.+(CH.sub.3).sub.2 CH.sub.2 C.sub.6                                   H.sub.4 Br] Br.sup.- 141-142.5                    29 [C.sub.2 H.sub.5 NHCSO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2                (CH.sub.2 -).sub.5 ] .sub.2 Br.sub.2.sup.-                                                             186.5-187                                         30 [C.sub.2 H.sub.5 NHCOO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2                C.sub.12 H.sub.25 ] Br.sup.-                                                                           67-69                                             31 [C.sub.2 H.sub.5 NHCOO(CH.sub.2).sub.6 N.sup.+(CH.sub.3).sub.2                C.sub.12 H.sub. 25 ] Br.sup.-                                                                          oil                                               32                                                                                ##STR9##                62-64                                             33                                                                                ##STR10##               oil                                               34                                                                                ##STR11##               oil                                               35 [CH.sub.3 NHCSO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2 C.sub.14              H.sub.29 ] Br.sup.-      73.5-77                                           36 [CH.sub.3 NHCSO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2 C.sub.10              H.sub.21 ] Br.sup.-      72-75                                             37 [ClC.sub.6 H.sub.4 NHCOO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2              C.sub.12 H.sub.25 ] Br.sup.-                                                                           177-179                                           38 [CH.sub.3 NHCOO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2 C.sub.12              H.sub.25 ] Br.sup.-      85.5-88                                           39 [CH.sub.3 NHCOO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2 C.sub.14              H.sub.29 ] Br.sup.-      107-108                                           40 [CH.sub.3 NHCOO(CH.sub.2).sub.3 N.sup.+(CH.sub.3).sub.2 C.sub.12              H.sub.25 ] Br.sup.-      72.5-77                                           41 [CH.sub.3 NHCOO(CH.sub.2).sub.3 N.sup.+(CH.sub.3).sub.2 C.sub.14              H.sub.29 ] Br.sup.-      75- 77                                            42 [C.sub.2 H.sub.5 NHCOO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2                C.sub.14 H.sub.29 ] Br.sup.-                                                                           98- 98.5                                          43 [C.sub.6 H.sub.11 NHCOO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2               C.sub.12 H.sub.25 ] Br.sup.-                                                                           128.5-131                                         44 [C.sub.6 H.sub.11 NHCOO(CH.sub.2).sub.2 N.sup.+(CH.sub.3).sub.2               C.sub.14 H.sub.29 ] Br.sup.-                                                                           123-128                                           __________________________________________________________________________

When submitted to a series of tests to determine their ability toprevent acid formation in incubated saliva both as is and/or as adsorbedupon protein and/or their ability to prevent growth of Streptococcus sp.HS-6 in a halo test, the compounds which are highly effective arenumbers 1-4, 6, 16, 21-24, 27, 30, 31, and 33-44 of the above list ofcompounds of the general formula.

The tests set forth in Examples 5 and 6 below evidence the effectivenessof the compounds of the invention in reducing caries and inhibitingformation of calculus.

EXAMPLE 5

The following test was conducted with compounds 2, 23, 30, and 40 of theabove list of compounds to determine their ability to reduce caries inanimals. Caries-susceptible hamsters bred either from the Keyes strainor the NIDR (National Institute for Dental Research) strain in groups of15 males and 15 females per control group and per each test group werefed ad lib a Mitchell cariogenic diet and received constant deionizedwater. Each day each hamster's teeth were swabbed 30 seconds by cottontipped swabs, the control group with water and each test group with itstest solution. After 6 weeks of swabbing the animals were sacrificed,and the defleshed heads were scored by a modified version of the Keyesscoring method. Mean averages and percentage changes from the controlwere determined and tested statistically to determine the significance.

    ______________________________________                                                            Caries                                                    Concentration      Reduction %                                                Compound                                                                              Test Solution  Males      Females                                     ______________________________________                                        23      1%             -55.4      -62.2                                               1%             -54.7      -33.9                                               0.5%           -44.2      -69.2                                               0.25%          -30.5      -57.8                                       30      1%             -71.4      -46.3                                       40      1%             -62.2      -58.6                                        2      0.5%           -23.2      -40.0                                       ______________________________________                                    

The results set forth above indicated the significant effectiveness ofthe quaternary compounds of the invention in reducing caries formation.

EXAMPLE 6

To show the effectiveness of compounds 2 and 23 in inhibiting thedevelopment of dental calculus, litter-mated Sprague-Dawley rats, 60days old, in groups of 15 males and 15 females were fed a Zipkin-McClurecalculus diet. For 2 to 3 weeks the teeth of each animal were swabbedfor thirty seconds each day with a test solution or water for thecontrol group. The animals were then sacrificed, defleshed and scored byBaer's method for calculus. The results were analyzed by Student's ttest and in the results quoted were 99% significant.

    ______________________________________                                                            Caries                                                           Concentration                                                                              Reduction %                                               Compound Test Solution  Males     Females                                     ______________________________________                                         2       0.5%           -71       -58                                         23       0.5%           -66       -40                                         ______________________________________                                    

The results set forth above indicated the significant effectiveness ofthe quaternary compounds of the invention in inhibiting formation oforal calculus.

When compounds of the instant invention are intended for use incompositions which reduce formation of caries and inhibit formation oforal calculus, they are typically incorporated in oral preparations ineffective amounts up to about 5% by weight, preferably 0.1-1% and mostpreferably 0.25-0.5% by weight of the oral preparation. Typically, theoral preparation is a dentifrice, such as a dental cream, tablet orpowder, containing as a vehicle about 20-95% by weight of awater-insoluble polishing material, preferably including water-insolublephosphate such as dicalcium phosphate, tricalcium phosphate,trimagnesium phosphate. The dentifrice may also include water; binderssuch as glycerine, sorbitol, propylene glycol, and polyethylene glycol400; detergents; gelling agents such as Irish moss and sodiumcarboxymethyl cellulose; additional antibacterial agents; coloring orwhitening agents; preservatives; silicones; chlorophyll compounds;additional ammoniated materials; flavoring or sweetening materials; andcompounds which provide fluorine-containing ion such as sodium fluoride,stannous fluoride and sodium monofluorophosphate.

The oral preparation may also be a liquid such as mouth rinse whichtypically contains 20-99% by weight of an aqueous alcohol vehicle, thealcohol being a cosmetically acceptable and nontoxic alcohol such asethanol or isopropyl alcohol and being present in amount of about 5-30%by weight of the oral preparation.

Such oral preparations are typically applied by brushing the teeth orrinsing the oral cavity for 30-90 seconds at least once daily. Typicaloral preparations of the invention which can be applied in this mannerare set forth below.

                  Example 7                                                       ______________________________________                                                 Dental Cream   %                                                     ______________________________________                                        Compound 23             0.50                                                  Nonionic detergent (Millox 120)                                                                       2.00                                                  Glycerine               22.00                                                 Sodium pyrophosphate    0.25                                                  Carboxymethyl cellulose 0.85                                                  Sodium saccharin        0.20                                                  Sodium benzoate         0.50                                                  Calcium carbonate (precipitated)                                                                      5.00                                                  Dicalcium phosphate dihydrate                                                                         46.75                                                 Flavor                  0.80                                                  Water                   21.15                                                 ______________________________________                                    

                  Example 8                                                       ______________________________________                                                 Mouth Wash     %                                                     ______________________________________                                        Compound 23              0.25                                                 Nonionic detergent (Pluronic F-68)                                                                    1.00                                                  Ethyl alcohol (containing flavor)                                                                     15.00                                                 Glycerine               10.00                                                 Saccharin               0.02                                                  Water                   73.73                                                 ______________________________________                                    

The antimicrobial effectiveness of the compounds of the invention wasevidenced in the tests set forth in Examples 9 and 10, below.

EXAMPLE 9

To illustrate the antibacterial character of compounds of the instantinvention the following halo test was performed. The cariogenic strainof streptococcus (HS6) obtained from NIDR was grown in fluidthioglycollate medium at 37° C. for 24 hours. A 2% inoculum was added tofluid thioglycollate agar at 45° C. After thorough mixing it wasdispersed in 20 ml. aliquots into sterile petri dishes. A 1/4-inchdiameter sterile paper disc was saturated with a solution of the testcompound and placed in firm contact with this agar. Then 20 ml. ofuninoculated fluid thioglycollate agar was poured into the petri dishesto reduce the oxygen tension. The dishes were incubated for 24 hours at37° C. The results which are averages of duplicate determinations arereported as mm. of inhibition of bacterial growth around the disc.

    ______________________________________                                        Halo Test Results                                                             Compound  Halo, mm.   Compound   Halo, mm.                                    ______________________________________                                        1         20          23         35                                           3         28          24         34                                           4         29          27         27                                           6         21          29         27                                           7         26          30         36                                           8         36          31         34                                           9         27          33         28                                           11        28          34         30                                           12        36          36         33                                           13        31          38         31                                           14        51          39         27                                           15        26          40         27                                           22        43          41         25                                           ______________________________________                                    

These halo tests evidenced anti- gram positive bacterial effectivenessof compounds of the invention.

EXAMPLE 10

The anti-microbial nature of the compounds was shown by a standard testtube serial dilution test in which an appropriate number of test tubesof broth containing decreasing concentrations of the test agent wasinoculated with the test organism. After a suitable period of incubationthe tubes were examined for the presence or absence of growth. Theactivity of the test agent was the lowest concentration which inhibitedthe growth of the organism and is expressed as the minimal inhibitoryconcentration (M.I.C.) in μg/ml.

    __________________________________________________________________________    Results (M.I.C.)                                                                    S.  S. mitis                                                                           B.   C.   C.   T.                                              Compound                                                                            aureus                                                                            (S-3)                                                                              subtilis                                                                           acnes                                                                              albicans                                                                           mentogrophytes                                  __________________________________________________________________________     1    1.56                                                                              1.56 0.2  1.56 6.25 125                                              6    0.39                                                                              3.12 0.39 0.78 6.25 3.12                                            16    0.39                                                                              0.39 0.39 0.78 1.56 0.98                                            17    <0.05                                                                             0.78 <0.05                                                                              1.56 3.12 3.12                                            18    0.39                                                                              <0.2 0.78 0.39 3.12 31.2                                            21    1.56                                                                              3.12 0.78 0.78 12.5 7.8                                             23    1.56                                                                              3.12 0.78 1.56 12.5 15.6                                            25    <0.05                                                                             0.78 0.2  1.56 0.78 1.56                                            27    0.78                                                                              3.12 0.2  1.56 12.5 6.25                                            32    <0.05                                                                             0.2  0.1  1.56 3.12 6.25                                            35    0.78                                                                              0.78 0.39 1.56 3.12 7.8                                             44    0.78                                                                              1.56 3.12 3.12 3.12 7.8                                             __________________________________________________________________________

These dilution tests evidence the effectiveness of compounds of theinvention against gram-positive bacteria and fungi.

When used against bacteria or fungi, compounds of the instant inventionmay be applied directly to the surface to be protected or may bedissolved in a pharmaceutical carrier. Typically, an effective amount,e.g. 0.1 to about 10% by weight of the compound, is included in an inertcarrier and a dispersing or surface active agent. Alternatively, aneffective amount, e.g. 0.1 to about 10% by weight, may be incorporatedinto a solid carrier which may be inert, such as talc, clay,diatomaceous earth, flour, etc.

Although this invention has been described with reference to specificexamples, it will be apparent to one skilled in the art that variousmodifications may be made thereto which fall within its scope.

I claim:
 1. A pharmaceutical composition comprising an effective amountof a chemical compound effective against gram positive microorganismsrepresented by the formula ##STR12## where R' is selected from the groupconsisting of an alkyl group containing 1 to 22 carbon atoms, a phenylgroup, a phenyl group substituted by an alkyl group containing 1 to 5carbon atoms and a phenyl group substituted by an alkoxy groupcontaining 1 to 5 carbon atoms and a phenyl group substituted byhalogen; selected from the group consisting of chlorine and bromineR"and R'" are each selected from the group consisting of an alkyl groupcontaining 1 to 2 carbon atoms; R"" is selected from the groupconsisting of an alkyl group containing 10 to 22 carbon atoms, a phenylgroup substituted by halogen selected from the group consisting ofchlorine and bromine, a phenyl group substituted by an alkyl groupcontaining 1 to 5 carbon atoms, a phenyl group substituted by an alkoxygroup containing 1 to 5 carbon atoms, a divalent phenyl group and amonovalent phenyl group; Y is selected from the group consisting ofoxygen and sulfur; Z is selected from the group consisting of oxygen andsulfur, at least one of Y and Z being sulfur; n is an integer 2 to 6;and X is a compatible anion selected from the group consisting ofchloride, bromide, iodide and methosulfate; said compound being admixedwith a pharmaceutically acceptable carrier.
 2. The pharmaceuticalcomposition as claimed in claim 1 wherein R"" as an alkyl group selectedfrom the group consisting of C₁₀ H₂₁, C₁₂ H₂₅ and C₁₄ H₂₉ and R' isselected from the group consisting of CH₃, C₂ H₅, C₄ H₉, C₆ H₅ and ClC₆H₄.
 3. The pharmaceutical composition as claimed in claim 1 wherein R""is selected from the group consisting of C₁₂ H₂₅ and C₁₈ H₃₇ and R' isselected from the group consisting of C₆ H₅ and ClC₆ H₄.
 4. Thepharmaceutical composition as claimed in claim 1 wherein Y is sulfur andZ is oxygen.
 5. The pharmaceutical composition as claimed in claim 1where said compound is represented by the formula: ##STR13##
 6. Thepharmaceutical composition as claimed in claim 1 wherein said compoundis represented by the formula: ##STR14##
 7. The pharmaceuticalcomposition as claimed in claim 1 wherein said compound is representedby the formula: ##STR15##
 8. The pharmaceutical composition as claimedin claim 1 wherein said compound is represented by the formula:##STR16##